The emergence and seasonal persistence of pathogenic H7N9 influenza viruses in China have raised concerns about the pandemic potential of these viruses due to their ability to bind to human sialic acid receptors and the development of resistance to neuraminidase inhibitors without a loss in fitness. Widespread H7N9 infections throughout the human population have a substantial impact on global health and economies. The pre-existing immunity to H7N9 strains from prior exposure to circulating human influenza viruses or influenza vaccination has yet to be investigated.
Influenza A viruses evade the human immune system by changing the antigenic regions of their surface glycoproteins using two mechanisms: antigenic drift (point mutations) and antigenic shift (gene segment reassortments) (Shaw M L and Palese P. Orthomyxoviruses. In: Knipe D M, Howley P M, eds. Fields Virology. Philadelphia, Pa., USA: Lippincott Williams and Wilkins; 2013; herein incorporated by reference in its entirety). Antigenic variation is further increased by divergent evolution as influenza virus strains recirculate continually among different host reservoirs, especially humans and avian species. The hemagglutinin (HA) glycoprotein is the main target of neutralizing antibodies, and is composed of an immuno-dominant globular head domain and a stalk domain (Kaur et al. Trends in immunology. 2011; 32(11):524-31; herein incorporated by reference in its entirety). HA subtypes are classified into two groups based on their antigenic properties, amino acid sequences and structural features (Air. Proc Natl Acad Sci USA. 1981; 78(12):7639-43; herein incorporated by reference in its entirety). Group 2 Influenza A viruses includes the H3 subtype, which further contains the seasonal H3N2 human strains, and the H7 subtype which contains highly pathogenic avian influenza (HPAI) A viruses (Medina & Garcia-Sastre. Nat Rev Microbiol. 2011; 9(8):590-603; herein incorporated by reference in its entirety). Previously, infections with H7 viruses, through exposure to poultry, generally resulted in uncomplicated influenza illness and/or mild conjunctivitis (demonstrated for H7N3), with only one fatal case observed during an outbreak in the Netherlands (H7N7) (Hirst et al. Emerg Infect Dis. 2004; 10(12):2192-5; Fouchier et al. Proc Natl Acad Sci USA. 2004; 101(5):1356-61; herein incorporated by reference in their entireties). However in 2013, a novel influenza A virus (H7N9), the reassortment product of various avian strains, emerged in China. This virus, associated with a high frequency of fatal human disease, appeared to have a wide dispersion and the potential for human-to-human transmission (Gao et al. N Engl J Med. 2013; 368(20):1888-97; Belser et al. Pathogenesis and transmission of avian influenza A (H7N9) virus in ferrets and mice. Nature. 2013; Watanabe et al. Characterization of H7N9 influenza A viruses isolated from humans. Nature. 2013; Morens et al. MBio. 2013; 4(4); Hu et al. Lancet. 2013; 381(9885):2273-9; Zhang et al. Science. 2013; 341(6144):410-4; herein incorporated by reference in their entireties). Although most publicized in 2013 (153 cases), the H7N9 virus shows a seasonal pattern with most infections occurring during the winter season. The incidence of infection continues to increase with nearly twice as many new H7N9 infections (301 cases) reported in 2014, totaling 454 cases, according to the World Health Organization as of July, 2014. These cases occurred in 12 provinces of China and imported cases in Malaysia and Taiwan. The incidence of H7N9 infections combined with its abilities to bind to human receptor orthologs and to develop resistance to neuraminidase inhibitors without fitness loss has raised concerns about the pandemic potential of H7N9 virus (Xu et al. Science. 2013; 342(6163):1230-5; Ramos et al. The Journal of general virology. 2013; 94 (Pt 11):2417-23; Hai et al. Nature communications. 2013; 4(2854.); herein incorporated by reference in their entireties).